The present invention relates to a novel process for preparing 2-(1,2,4-triazol-1-yl)-ethanols having microbicidal, in particular fungicidal, properties.
It is already known that numerous 2-(1,2,4-triazol-1-yl)-ethanols can be prepared by reacting appropriately substituted oxiranes with 1,2,4-triazole in the presence of a base and a diluent. However, this process has the disadvantage that, in addition to the desired 1,2,4-triazol-1-yl compounds (=xe2x80x9casymmetric triazolexe2x80x9d), varying proportions of interfering 1,3,4-triazol-1-yl derivatives (=xe2x80x9csymmetric triazolexe2x80x9d) are also obtained (cf. Tetrahedron Lett. 30 (1989) 4013-4016). Naturally, this reduces the yield of the 1,2,4-triazol-1-yl derivative. Moreover, removal of the interfering 1,3,4-triazol-1-yl compound renders work-up more difficult, so that the yield of 1,2,4-triazol-1-yl derivative is frequently reduced even further.
It is also already known that 1,2,4-triazoles which are substituted in the 1-position can be obtained by reacting substituted hydrazines with [2-aza-3-(dimethylamino)-2-propene-1-ylidene]-dimethylimmonium chloride (xe2x80x9cGold""s reagentxe2x80x9d) (cf. Angew. Chem. 72 (1960) 956-959). However, the yields are not satisfactory. A further disadvantage is the fact that 2 mol of dimethylamine are produced per mole of triazolyl derivative.
It is furthermore already known that 1,2,4-triazoles which are substituted in the 1-position can be obtained by reacting hydrazine derivatives with formamidine acetate (cf. xe2x80x9cNxe2x80x94Cxe2x80x94N Chemicals; Formamidine; Building block for heterocycles and intermediatesxe2x80x9d, company publication from SKW Trostberg AG, 1989). Thus, 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(1,2,4-triazol-1-yl)-propane-2-ol can be synthesized by reacting 2-(1-chloro-cyclopropyl)-2-(2-chlorobenzyl)-oxirane with hydrazine hydrate, followed by reaction of the resulting 2-(1-chloro-cycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxy-propyl-hydrazine with formamidine acetate (cf. DE-A 40 30 039). However, it is disadvantageous that the yield of the desired target product is relatively low.
It has now been found that 2-(1,2,4-triazol-1-yl)-ethanols of the formula 
in which
A1 and A2 independently of one another represent a direct bond, represent optionally halogen-substituted alkanediyl, represent optionally halogen-substituted alkenediyl, represented optionally halogen-substituted alkinediyl or represent alkanediyl in which a methylene group is replaced by oxygen,
R1 and R2 independently of one another represent hydrogen, represent optionally substituted cycloalkyl or represent optionally substituted aryl and
R3 and R4 independently of one another represent hydrogen or represent optionally substituted alkyl or
R3 and R4 together with the carbon atom to which they are attached represent optionally substituted cycloalkyl, or
R1, A1 and R3 together with the carbon atoms to which they are attached represent cycloalkyl,
A2 represents a direct bond, represents optionally halogen-substituted alkanediyl, represents optionally halogen-substituted alkenediyl, represents optionally halogen-substituted alkinediyl or represents alkanediyl in which one methylene group has been replaced by oxygen,
R2 represents hydrogen, represents optionally substituted cycloalkyl or represents optionally substituted aryl and
R4 represents hydrogen or represents optionally substituted alkyl, or
R3 and R4 represent hydrogen and the groups
R1xe2x80x94A1xe2x80x94 and R2xe2x80x94A2xe2x80x94 together with the carbon atom to which they are attached represent a radical of the formula 
can be prepared by reacting hydrazine derivatives of the formula 
in which
A1, A2, R1, R2, R3 and R4 are as defined above
with N-dihalogenomethyl-formamidinium halide of the formula 
in which
X represents chlorine or bromine,
if appropriate in the presence of a diluent.
It is extremely surprising that 2-(1,2,4-triazol-1-yl)-ethanols of the formula (I) can be prepared by the process according to the invention in a smooth reaction, since the prior art indicated that there would be interfering side-reactions and decomposition of N-dihalogenomethyl-formamidinium halide of the formula (III). Thus, it follows from Ber. dtsch. Chem. Ges. 16 (1883) 308-311 that N-dichloromethyl-formamidinium chloride is decomposed by water or alcohols. Furthermore, Chem. Ber. 35, (1902) 2496-2511 describes that one equivalent of N-dichloromethylformamidinium chloride reacts easily and completely with two equivalents of a primary amine of the formula Rxe2x80x94NH2 with elimination of three equivalents of hydrogen chloride to give one equivalent of formamidine and one equivalent of disubstituted formamidine of the formula Rxe2x80x94Nxe2x95x90CHxe2x80x94NHxe2x80x94R. The reaction of o-phenylenediamine with N-dichloromethyl-formamidinium chloride gives benzimidazole (cf. Chem. Ber. 35 (1902), 2496-2511). Phenylhydrazine reacts with N-dichloromethylformamidinium chloride like primary amine; however, the formamidine derivative formed is oxidized further by atmospheric oxygen or a third equivalent of phenylhydrazine to give diphenylformazane of the formula Phxe2x80x94Nxe2x95x90Nxe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94Ph (cf. Chem. Ber. 35 (1902), 2496-2511). The formation of 1-phenyl-1,2,4-triazole from phenylhydrazine and N-dichloromethyl-formamidinium chloride has not been reported. Taking into account these known reactions, it was without any doubt contrary to expectations that the reaction according to the invention would give the desired type of products in high yield.
The process according to the invention has a number of advantages. Thus, as already mentioned, it makes possible the synthesis of 2-(1,2,4-triazol-1-yl)-ethanols of the formula (I) in high yield, free from the corresponding xe2x80x9csymmetricxe2x80x9d triazole derivatives. Moreover, it is favourable that the required starting materials and reaction components can be prepared in a simple manner and are available even in relatively large amounts. Finally, it is a further advantage that the yields are higher than those for comparable reactions of hydrazines with formamidine acetate or xe2x80x9cGold""s reagentxe2x80x9d. Compared to the use of xe2x80x9cGold""s reagentxe2x80x9d, it is furthermore favourable that the reactions according to the invention with N-dihalogenomethyl-formamidinium halide produce only hydrogen halide and ammonia.
Using [1-(2-chlorophenyl)-2-(1-chloro-cyclopropyl)-2-hydroxy]-propylhydrazine hydrochloride and N-dichloromethyl-formamidinium chloride as starting materials, the course of the process according to the invention can be illustrated by the formula scheme below. 
The formula (II) provides a general definition of the hydrazine derivatives required as starting materials for carrying out the process according to the invention. Preference is given to using hydrazine derivatives of the formula (II) in which
A1 represents a direct bond, represents optionally halogen-substituted, straight-chain or branched alkanediyl having 1 to 4 carbon atoms, represents optionally halogen-substituted, straight-chain or branched alkenediyl having 2 to 4 carbon atoms, represents optionally halogen-substituted straight-chain or branched alkinediyl having 2 to 4 carbon atoms or represents straight-chain or branched alkanediyl in which one methylene group has been replaced by oxygen, having 2 to 4 chain members,
A2 represents a direct bond, represents optionally halogen-substituted straight-chain or branched alkanediyl having 1 to 6 carbon atoms, represents optionally halogen-substituted straight-chain or branched alkenediyl having 2 to 6 carbon atoms or represents optionally halogen-substituted straight-chain or branched alkinediyl having 2 to 6 carbon atoms,
R1 represents cycloalkyl having 3 to 7 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and/or alkyl having 1 to 4 carbon atoms or represents aryl having 6 to 10 carbon atoms which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, alkyl having 1 to 4 carbon atoms, cyano, nitro, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms, halogenoalkoxy having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms or halogenoalkylthio having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms,
R2 represents hydrogen or represents cycloalkyl having 3 to 7 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and alkyl having 1 to 4 carbon atoms or represents aryl having 6 to 10 carbon atoms which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, alkyl having 1 to 4 carbon atoms, cyano, nitro, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms, halogenoalkoxy having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms and halogenoalkylthio having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms, and
R3 and R4 independently of one another represent hydrogen or alkyl having 1 to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and alkoxy having 1 or 2 carbon atoms or
R3 and R4 together with the carbon atom to which they are attached represent cycloalkyl having 3 to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and alkyl having 1 to 4 carbon atoms, or
R1, A1 and R3 together with the carbon atoms to which they are attached represent cycloalkyl having 3 to 6 carbon atoms,
A2 represents a direct bond,
R2 represents hydrogen or represents cycloalkyl having 3 to 7 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and alkyl having 1 to 4 carbon atoms or represents aryl having 6 to 10 carbon atoms which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, alkyl having 1 to 4 carbon atoms, cyano, nitro, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms, halogenoalkoxy having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms or halogenoalkylthio having 1 to 4 carbon atoms and 1 to 9 fluorine, chlorine and/or bromine atoms, and
R4 represents hydrogen or represents alkyl having 1 to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and alkoxy having 1 or 2 carbon atoms, or
R3 and R4 represent hydrogen and the groups
R1xe2x80x94A1xe2x80x94 and R2xe2x80x94A2xe2x80x94 together with the carbon atoms to which they are attached represent a radical of the formula 
Particular preference is given to hydrazine derivatives of the formula (II) in which
A1 represents a single bond, represents methylene, ethane-1,1-diyl, ethane-1,2-diyl, ethene-1,2-diyl, ethine-1,2-diyl or xe2x80x94Oxe2x80x94CH2, where the CH2 group is attached to the carbinol carbon atom,
A2 represents a direct bond or represents methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, butane-2,2-diyl, 2-methyl-propane-1,2-diyl, ethylene-1,2-diyl or ethine-1,2-diyl, each of which is optionally mono- or disubstituted by fluorine and/or chlorine,
R1 represents cycloalkyl having 3 to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl or represents phenyl or naphthyl, each of which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, methoxy, ethoxy, methylthio, ethylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and difluoromethylthio,
R2 represents hydrogen or represents cycloalkyl having 3 to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl or represents phenyl or naphthyl, each of which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, methoxy, ethoxy, methylthio, ethylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and difluoromethylthio,
R3 and R4 independently of one another represent hydrogen, methyl or ethyl or
R3 and R4 together with the carbon atom to which they are attached represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl or
R1, A1 and R3 together with the carbon atoms to which they are attached represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
A2 represents a direct bond
R2 represents hydrogen or represents cycloalkyl having 3 to 6 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl, or represents phenyl or naphthyl, each of which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, methoxy, ethoxy, methylthio, ethylthio, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and difluoromethylthio and
R4 represents hydrogen, methyl or ethyl, or
R3 and R4 represent hydrogen and the groups
R1xe2x80x94A1xe2x80x94 and R2xe2x80x94A2xe2x80x94 together with the carbon atom to which they are attached represent a radical of the formula 
The hydrazine derivatives of the formula (II) are known or can be prepared by known methods. Thus, hydrazine derivatives of the formula (II) can be obtained by reacting oxiranes of the formula 
in which
A1, A2, R1, R2, R3 and R4 are as defined above with hydrazine or hydrazine hydrate (cf. J. Org. Chem. 61 (1996) 4125; J. Amer. Chem. Soc. 99 (1977) 1172; Bull. Soc. Chim. Fr. 1947 850; and Bull. Soc. Chim. Fr. 1939, 708).
The oxiranes of the formula (IV) are known or can be prepared by known methods.
The hydrazine derivatives of the formula (II) can be employed either as free bases or in the form of their salts, such as, for example, their hydrochlorides, hydrobromides or hydrogen sulphates. Preference is given to using the hydrochlorides.
The formula (III) provides a general definition of the N-dihalogenomethyl-formamidinium halides furthermore required as starting materials for carrying out the process according to the invention. In this formula, X preferably represents chlorine.
The N-dihalogenomethyl-formamidinium halides (III) are known or can be prepared by known methods. Thus, N-dihalogenomethyl-formamidinium halides of the formula (III) are obtained by reacting 2 equivalents of hydrocyanic acid with 3 equivalents of hydrogen halide. The N-dihalogenomethyl-formamidinium halides are also referred to as sesquihydrohalides of hydrocyanic acid. N-Dichloromethyl-formamidinium chloride can be prepared, for example, by introducing dry hydrogen chloride into a solution, cooled to about xe2x88x9210xc2x0 C., of hydrocyanic acid in a diluent, such as, for example, ethyl acetate (cf. Ber. dtsch. Chem. Ges. 16 (1883) 308-311). N-Dichloromethyl-formamidinium chloride can be represented by the formula 
However, other structures are also possible (cf. Chem. Ber. 99 (1966), 431-444). For the sake of simplicity, only the formula (III-1) is used hereinafter, but this does not imply that a decision about the actual structure of the sesquihydrochloride of bydrocyanic acid has been made.
Suitable diluents for carrying out the process according to the invention are, in principle, all customary inert organic solvents. Preference is given to using carboxylic esters, such as methyl formate, ethyl formate, ethyl acetate and methyl acetate, furthermore ethers, such as tert-butyl methyl ether and 1,4-dioxane, furthermore N,N-disubstituted acid amides, such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, and additionally aromatic or aliphatic hydrocarbons, such as toluene, xylene, cyclohexane and methylcyclohexane. Particular preference is given to methyl acetate, ethyl acetate and toluene.
When carrying out the process according to the invention, the reaction temperatures can be varied within a relatively wide range. Frequently, the upper limit of the temperature range is given by the decomposition temperature of the hydrazine derivative of the formula (II). In general, the process is carried out at temperatures between 20 and 200xc2x0 C., preferably between 30 and 150xc2x0 C.
The process according to the invention is generally carried out under atmospheric pressure. However, it is also possible to operate under elevated or reduced pressure.
When carrying out the process according to the invention, the ratio in which the reaction components are employed can be varied within a relatively wide range. For economical reasons, at least 1 mol of N-dihalogenomethyl-formamidinium halide of the formula (III) is employed per mole of hydrazine derivative of the formula (II) or its salt. However, it is also possible to use less than 1 mol of N-dihalogenomethyl-formamidinium halide. Preferably, the N-dihalogenomethylformamidinium halide of the formula (III) is employed in an excess of from 1 to 30 mol %, particularly preferably from 5 to 20 mol %. Work-up is carried out by customary methods. In general, the reaction mixture is admixed with water and an organic solvent which is sparingly miscible with water, the organic phase is separated off, the aqueous phase is extracted with an organic solvent and the combined organic phases are dried and concentrated. Any impurities which may still be present can be removed by customary methods, for example by recrystallization, distillation or chromatographically.
The 2-(1,2,4-triazol-1-yl)-ethanols of the formula (I) preparable by the process according to the invention are known (cf. EP-A 0 040 345 and EP-A 0 297 345).
The 2-(1,2,4-triazol-1-yl)-ethanols of the formula (I) have microbicidal, in particular fungicidal, properties.
The practice of the process according to the invention is illustrated by the examples below.